Mitochondrial Depletion Syndromes

Abstract

Mitochondrial DNA (mtDNA) depletion syndromes (MDDSs) are a clinically and molecularly heterogeneous group of mitochondrial disorders characterised by severely reduced mtDNA copy number in affected tissues. Phenotypically, MDDSs manifest as Alpers‐Huttenlocher disease (AHD), mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), infantile‐onset spinocerebellar ataxia (IOSCA), hepatocerebral MDDS, encephalomyopathic MDDS or myopathic MDDS. Genotypically, MDDSs are due to mutations in nine genes (POLG1, C10orf2/PEO1, DGUOK, MPV17, TK2, RRM2B, SUCLA2, SUCLG1, TYMP). Except for AHD and IOSCA, MDDSs are genetically heterogeneous. The diagnosis is established upon clinical and instrumental investigations and demonstration of depleted mtDNA in affected tissues, such as muscle, liver, brain or intestines. Treatment is symptomatic in the vast majority of the cases and can substantially relief clinical manifestations. A causal therapeutic approach with allogeneic, hematopoietic stem‐cell transplantation is available for MNGIE. MDDSs have a poor prognosis in the majority of the cases. The outcome is usually better the later the onset of the MDDSs.

Key Concepts

  • Paediatric and adult neurologist must be aware of multisystem mitochondrial depletion syndromes (MDDSs).
  • MDDSs predominantly manifest in the brain, muscle, liver, kidneys and intestines.
  • In addition to mutations in one of the nine classical genes associated with MDDS, it may be caused by mutations in other genes as well.
  • MDDSs are diagnosed by demonstration of mtDNA depletion upon biopsy of the most affected tissues.
  • mtDNA copy number may be normal in tissues hardly phenotypically affected.
  • Clinical severity of MDDS depends on the amount of the residual mtDNA copy number.
  • MDDSs may rarely also occur in adults due to mutations in nuclear genes other than the nine classical ones.

Keywords: mitochondrial DNA; depletion; copy number; mitochondrial syndromes; mitochondrial disorders

Figure 1. Schematic presentation of proteins involved in mitochondrial nucleotide pools maintenance and mtDNA replication. Reproduced with permission from El‐Hattab and Scaglia (2013) © Springer.
close

References

Al‐Hassnan ZN, Al‐Dosary M, Alfadhel M, et al. (2015) ISCA2 mutation causes infantile neurodegenerative mitochondrial disorder. Journal of Medical Genetics 52: 186–94.

Al‐Hussaini A, Faqeih E, El‐Hattab AW, et al. (2014) Clinical and molecular characteristics of mitochondrial DNA depletion syndrome associated with neonatal cholestasis and liver failure. Journal of Pediatrics 164: 553–559.e1‐2.

Antonenkov VD, Isomursu A, Mennerich D, et al. (2015) The human mitochondrial DNA depletion syndrome gene MPV17 encodes a non‐selective channel that modulates membrane potential. Journal of Biological Chemistry 290: 13840–61.

Bijarnia‐Mahay S, Mohan N, Goyal D and Verma IC (2014) Mitochondrial DNA depletion syndrome causing liver failure. Indian Pediatrics 51: 666–8.

Boesch P, Lightowlers RN and Chrzanowska‐Lightowlers ZMA (2008) Mitochondrial DNA and diseases. In: eLS. Chichester: John Wiley & Sons Ltd http://www.els.net. DOI: 10.1002/9780470015902.a0001462.pub2.

Bulst S, Abicht A, Holinski‐Feder E, et al. (2009) In vitro supplementation with dAMP/dGMP leads to partial restoration of mtDNA levels in mitochondrial depletion syndromes. Human Molecular Genetics 18: 1590–9.

Copeland WC (2014) Defects of mitochondrial DNA replication. Journal of Child Neurology 29: 1216–24.

Dimmock D, Tang LY, Schmitt ES and Wong LJ (2010) Quantitative evaluation of the mitochondrial DNA depletion syndrome. Clinical Chemistry 56: 1119–27.

Douglas GV, Wiszniewska J, Lipson MH, et al. (2011) Detection of uniparental isodisomy in autosomal recessive mitochondrial DNA depletion syndrome by high‐density SNP array analysis. Journal of Human Genetics 56: 834–9.

El‐Hattab AW and Scaglia F (2013) Mitochondrial DNA depletion syndromes: review and updates of genetic basis, manifestations, and therapeutic options. Neurotherapeutics 10: 186–198.

Fernández‐Millán P, Lázaro M, Cansız‐Arda Ş, et al. (2015) The hexameric structure of the human mitochondrial replicative helicase Twinkle. Nucleic Acids Research 43: 4284–95.

Finsterer J and Ahting U (2013) Mitochondrial depletion syndromes in children and adults. Canadian Journal of Neurological Sciences 40: 635–44.

Ghezzi D and Zeviani M (2011) Mitochondrial disorders: nuclear gene mutations. In: eLS. Chichester: John Wiley & Sons Ltd http://www.els.net. DOI: 10.1002/9780470015902.a0005540.pub2.

Gorman GS and Taylor RW (2014) RRM2B‐related mitochondrial disease. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, Bird TD, Dolan CR, Fong CT, Smith RJH and Stephens K (eds) GeneReviews® [Internet]. Seattle, WA: University of Washington; 1993–2015.

Hakonen AH, Goffart S, Marjavaara S, et al. (2008) Infantile‐onset spinocerebellar ataxia and mitochondrial recessive ataxia syndrome are associated with neuronal complex I defect and mtDNA depletion. Human Molecular Genetics 17: 3822–35.

Hazard FK, Ficicioglu CH, Ganesh J and Ruchelli ED (2013) Liver pathology in infantile mitochondrial DNA depletion syndrome. Pediatric and Developmental Pathology 16: 415–24.

Hirano M, Martí R, Casali C, et al. (2006) Allogeneic stem cell transplantation corrects biochemical derangements in MNGIE. Neurology 67: 1458–60.

Johansson M and Karlsson A (1996) Cloning and expression of human deoxyguanosine kinase cDNA. Proceedings of the National Academy of Sciences 93: 7258–62.

Kaji S, Murayama K, Nagata I, et al. (2009) Fluctuating liver functions in siblings with MPV17 mutations and possible improvement associated with dietary and pharmaceutical treatments targeting respiratory chain complex II. Molecular Genetics and Metabolism 97: 292–6.

Kalko SG, Paco S, Jou C, et al. (2014) Transcriptomic profiling of TK2 deficient human skeletal muscle suggests a role for the p53 signalling pathway and identifies growth and differentiation factor‐15 as a potential novel biomarker for mitochondrial myopathies. BMC Genomics 15: 91. DOI: 10.1186/1471-2164-15-91.

Kasapkara CS, Tümer L, Küçükçongar A, et al. (2013) DGUOK‐related mitochondrial DNA depletion syndrome in a child with an early diagnosis of glycogen storage disease. Journal of Pediatric Gastroenterology and Nutrition 57: e28–e29.

Knierim E, Seelow D, Gill E, von Moers A and Schuelke M (2015) Clinical application of whole exome sequencing reveals a novel compound heterozygous TK2‐mutation in two brothers with rapidly progressive combined muscle‐brain atrophy, axonal neuropathy, and status epilepticus. Mitochondrion 20: 1–6.

Kollberg G, Moslemi AR, Darin N, et al. (2006) POLG1 mutations associated with progressive encephalopathy in childhood. Journal of Neuropathology and Experimental Neurology 65: 758–68.

Komulainen T, Hautakangas MR, Hinttala R, et al. (2015) Mitochondrial DNA depletion and deletions in paediatric patients with neuromuscular diseases: novel phenotypes. JIMD Reports 23: 91–100.

Kowluru A, Tannous M and Chen HQ (2002) Localization and characterization of the mitochondrial isoform of the nucleoside diphosphate kinase in the pancreatic beta cell: evidence for its complexation with mitochondrial succinyl‐CoA synthetase. Archives of Biochemistry and Biophysics 398: 160–9.

Lee Y‐S, Kennedy WD and Yin YW (2009) Structural insight into processive human mitochondrial DNA synthesis and disease‐related polymerase mutations. Cell 139: 312–24.

Liu Z, Fang F, Ding C, et al. (2014) SUCLA2‐related encephalomyopathic mitochondrial DNA depletion syndrome: a case report and review of literature. Zhonghua Er Ke Za Zhi 52: 817–21.

Liu Y, Li X, Wang Q, et al. (2015) Five novel SUCLG1 mutations in three Chinese patients with succinate‐CoA ligase deficiency noticed by mild methylmalonic aciduria. Brain Dev pii: S0387‐7604(15)00096‐0. DOI: 10.1016/j.braindev.2015.05.002.

Löllgen S and Weiher H (2015) The role of the Mpv17 protein mutations of which cause mitochondrial DNA depletion syndrome (MDDS): lessons from homologs in different species. Biological Chemistry 396: 13–25.

Matilainen S, Isohanni P, Euro L, et al. (2015) Mitochondrial encephalomyopathy and retinoblastoma explained by compound heterozygosity of SUCLA2 point mutation and 13q14 deletion. European Journal of Human Genetics 23: 325–30.

Montassir H, Maegaki Y, Murayama K, et al. (2015) Myocerebrohepatopathy spectrum disorder due to POLG mutations: a clinicopathological report. Brain Dev 37: 719–24.

Morino H, Pierce SB, Matsuda Y, et al. (2014) Mutations in Twinkle primase‐helicase cause Perrault syndrome with neurologic features. Neurology 83: 2054–61.

Naviaux RK and Nguyen KV (2005) POLG mutations associated with Alpers syndrome and mitochondrial DNA depletion. Annals of Neurology 58: 491.

Nobre S, Grazina M, Silva F, et al. (2012) Neonatal liver failure due to deoxyguanosine kinase deficiency. BMJ Case Report pii: bcr1220115317. DOI: 10.1136/bcr.12.2011.5317.

Nogueira C, Almeida LS, Nesti C, et al. (2014) Syndromes associated with mitochondrial DNA depletion. Italian Journal of Pediatrics 40: 34. DOI: 10.1186/1824-7288-40-34.

Ostergaard E (2009) SUCLA2‐related mitochondrial DNA depletion syndrome, encephalomyopathic form, with mild methylmalonic aciduria. In: Pagon RA, Bird TD, Dolan CR, Stephens K and Adam MP (eds) GeneReviews™ [Internet]. Seattle, WA: University of Washington Available from http://www.ncbi.nlm.nih.gov/books/NBK6803/.

Parini R, Furlan F, Notarangelo L, et al (2009) Glucose metabolism and diet‐based prevention of liver dysfunction in MPV17 mutant patients. Journal of Hepatology 50: 215–21.

Peedikayil MC, Kagevi EI, Abufarhaneh E, Alsayed MD and Alzahrani HA (2015) Mitochondrial neurogastrointestinal encephalomyopathy treated with stem cell transplantation: a case report and review of literature. Hematology/Oncology and Stem Cell Therapy 8: 85–90.

Piekutowska‐Abramczuk D, Pronicki M, Strawa K, et al. (2014) Novel c.191C>G (p.Pro64Arg) MPV17 mutation identified in two pairs of unrelated Polish siblings with mitochondrial hepatoencephalopathy. Clinical Genetics 85: 573–7.

Poulton J and Bindoff L (2001) Mitochondrial respiratory chain disorders. In: eLS. Chichester: John Wiley & Sons Ltd http://www.els.net. DOI: 10.1038/npg.els.0002287.

Roos S, Lindgren U, Ehrstedt C, Moslemi AR and Oldfors A (2014) Mitochondrial DNA depletion in single fibers in a patient with novel TK2 mutations. Neuromuscular Disorders 24: 713–20.

Saneto RP, Cohen BH, Copeland WC and Naviaux RK (2013) Alpers‐Huttenlocher syndrome. Pediatric Neurology 48: 167–78.

Sarig O, Goldsher D, Nousbeck J, et al. (2013) Infantile mitochondrial hepatopathy is a cardinal feature of MEGDEL syndrome (3‐methylglutaconic aciduria type IV with sensorineural deafness, encephalopathy and Leigh‐like syndrome) caused by novel mutations in SERAC1. American Journal of Medical Genetics. Part A 161A: 2204–15.

Scaglia F, Dimmock D and Wong LJ (2009) DGUOK‐related mitochondrial DNA depletion syndrome, hepatocerebral form. In: Pagon RA, Bird TD, Dolan CR, Stephens K and Adam MP (eds) GeneReviews™ [Internet]. Seattle, WA: University of Washington Available from http://www.ncbi.nlm.nih.gov/books/NBK7040/.

Scalais E, Francois B, Schlesser P, et al (2012) Polymerase gamma deficiency (POLG): clinical course in a child with a two stage evolution from infantile myocerebrohepatopathy spectrum to an Alpers syndrome and neuropathological findings of Leigh's encephalopathy. European Journal of Paediatric Neurology 16: 542–8.

Simon M, Chang RC, Bali DS, et al. (2014) Abnormalities in glycogen metabolism in a patient with alpers' syndrome presenting with hypoglycemia. JIMD Reports 14: 29–35.

Spelbrink JN, Li FY, Tiranti V, et al. (2001) Human mitochondrial DNA deletions associated with mutations in the gene encoding Twinkle, a phage T7 gene 4‐like protein localized in mitochondria. Nature Genetics 28 (suppl 3): 223–31.

Spinazzola A and Zeviani M (2007) Disorders of nuclear‐mitochondrial intergenomic communication. Bioscience Reports 27 (suppl 1–3): 39–51.

Stojanovic V, Mayr JA, Sperl W, et al. (2013) Infantile peripheral neuropathy, deafness, and proximal tubulopathy associated with a novel mutation of the RRM2B gene: case study. Croatian Medical Journal 54: 579–84.

Sun R and Wang L (2014) Thymidine kinase 2 enzyme kinetics elucidate the mechanism of thymidine‐induced mitochondrial DNA depletion. Biochemistry 53: 6142–50.

Thomas M, Salpietro V, Canham N, et al. (2015) Mitochondria DNA depletion syndrome in a infant with multiple congenital malformations, severe myopathy, and prolonged postoperative paralysis. Journal of Child Neurology 30: 654–8.

Uusimaa J, Hinttala R, Rantala H, et al. (2008) Homozygous W748S mutation in the POLG1 gene in patients with juvenile‐onset Alpers syndrome and status epilepticus. Epilepsia 49: 1038–45.

Yu M (2012) Mitochondrial DNA copy number alterations in human cancers. In: eLS. Chichester: John Wiley & Sons Ltd http://www.els.net. DOI: 10.1002/9780470015902.a0024873.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Finsterer, Josef, and Wakil, Salma M(Dec 2015) Mitochondrial Depletion Syndromes. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0025731]